4UUQ

Crystal structure of human mono-glyceride lipase in complex with SAR127303

Summary for 4UUQ

• Entry DOI: 10.2210/pdb4uuq/pdb
• Descriptor: MONOGLYCERIDE LIPASE, 4-({[(4-chlorophenyl)sulfonyl]amino}methyl)piperidine-1-carboxylic acid (3 entities in total)
• Functional Keywords: hydrolase
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 2
• Total formula weight: 71250.63

Authors

Griebel, G.,Pichat, P.,Beeske, S.,Leroy, T.,Redon, N.,Francon, D.,Bert, L.,Even, L.,Lopez-Grancha, M.,Tolstykh, T.,Sun, F.,Yu, Q.,Brittain, S.,Arlt, H.,He, T.,Zhang, B.,Wiederschain, D.,Bertrand, T.,Houtman, J.,Rak, A.,Vallee, F.,Michot, N.,Auge, F.,Menet, V.,Bergis, O.E.,George, P.,Avenet, P.,Mikol, V.,Didier, M.,Escoubet, J. (deposition date: 2014-07-30, release date: 2015-01-21, Last modification date: 2024-10-23)

Primary citation

Griebel, G.,Pichat, P.,Beeske, S.,Leroy, T.,Redon, N.,Jacquet, A.,Francon, D.,Bert, L.,Even, L.,Lopez-Grancha, M.,Tolstykh, T.,Sun, F.,Yu, Q.,Brittain, S.,Arlt, H.,He, T.,Zhang, B.,Wiederschain, D.,Bertrand, T.,Houtmann, J.,Rak, A.,Vallee, F.,Michot, N.,Auge, F.,Menet, V.,Bergis, O.E.,George, P.,Avenet, P.,Mikol, V.,Didier, M.,Escoubet, J.
Selective Blockade of the Hydrolysis of the Endocannabinoid 2-Arachidonoylglycerol Impairs Learning and Memory Performance While Producing Antinociceptive Activity in Rodents.
Sci.Rep., 5:7642-, 2015

PubMed Abstract: Monoacylglycerol lipase (MAGL) represents a primary degradation enzyme of the endogenous cannabinoid (eCB), 2-arachidonoyglycerol (2-AG). This study reports a potent covalent MAGL inhibitor, SAR127303. The compound behaves as a selective and competitive inhibitor of mouse and human MAGL, which potently elevates hippocampal levels of 2-AG in mice. In vivo, SAR127303 produces antinociceptive effects in assays of inflammatory and visceral pain. In addition, the drug alters learning performance in several assays related to episodic, working and spatial memory. Moreover, long term potentiation (LTP) of CA1 synaptic transmission and acetylcholine release in the hippocampus, two hallmarks of memory function, are both decreased by SAR127303. Although inactive in acute seizure tests, repeated administration of SAR127303 delays the acquisition and decreases kindled seizures in mice, indicating that the drug slows down epileptogenesis, a finding deserving further investigation to evaluate the potential of MAGL inhibitors as antiepileptics. However, the observation that 2-AG hydrolysis blockade alters learning and memory performance, suggests that such drugs may have limited value as therapeutic agents.

PubMed: 25560837
DOI: 10.1038/SREP07642

Experimental method

X-RAY DIFFRACTION (2.36 Å)